Reversible Photochromism of 4,4'-Disubstituted 2,2'-Bipyridine in the Presence of SO3.

We report an unusual photochromic behavior of 4,4'-disubstituted-2,2'-bipyridine. It was found that in the presence of a SO3 source and HCl, 2,2'-bipyridine-4,4'-dibutyl ester undergoes a color change from yellow to magenta in solution with maximum absorbance at 545 nm upon irradiation with 395 nm light. The photochromism is thermally reversible in solution. Different from the known bipyridine-based photoswitching pathways, the photo response does not involve any metal which form colored complexes or the formation of colored free radical cations like the photo-reduction of viologens. A combination of experimental and computational analysis was used to probe the mechanism. The results suggest the colored species to be a complex formed between N-oxide of the 2,2'-bipyridine-4,4'-dibutyl ester and SO2; the N-oxide and SO2 are formed from photoactivated oxidation of the bipyridine with SO3 serving as the oxygen source. This complex represents a new addition to the library of photoswitches that is easy to synthesize, reversible in solution, and of high fatigue resistance, making it a promising candidate for applications in photo-switchable materials and SO3 detection. We also demonstrated experimentally similar photochromic behaviors with 2,2'-bipyridine-containing polymers.

Evaluating the Impact of Telehealth on Carbon Footprint During Three Phases of the Pandemic at a Rural Academic Medical Center.

Background: Climate change is primarily driven by greenhouse gases, such as carbon dioxide (CO2). Telehealth visits have been found to mitigate carbon emissions by reducing patient and physician transport. Dartmouth Hitchcock Medical Center (DHMC) is the most rural academic medical center in the country, serving a population where the majority of patients reach the hospital by car. No large study or systematic review has evaluated the impact of telehealth visits on CO2 emissions (CO2e) across multiple specialties in a purely rural setting. Further, no sizable rurally focused study has compared CO2e avoided during the various stages of the pandemic. Methods: We extracted data for all outpatient telehealth visits at DHMC from three periods: prepandemic, early pandemic, and late pandemic. The extracted data included the pandemic stage of the virtual visit, the type of visit (video or telephone), the specialty, and the distance from the patient's home to DHMC. Results: The total CO2e avoided among all three pandemic stages analyzed in this study was 23,658,898 kg (n = 251,832). During period 1, the mean driving distance = 159.0 miles; CO2e avoided per encounter = 128.3 kg; period 2, mean distance = 84.85 miles; average CO2e avoided per encounter = 68.47 CO2e kg; and period 3, mean distance = 112.9 miles; average CO2e avoided per encounter = 91.08 kg. Conclusions: This data supported long distances to the medical center and large savings in CO2e avoided across multiple specialties that spanned all pandemic periods. Further, this level of averted emissions could translate to over $3M in saved fuel costs and the avoidance of six excess deaths. While discussions of the future of telehealth commonly focus on access, use cases, technology, costs, and satisfaction, the impact on carbon footprint is an additional important metric, particularly in largely rural regions.

Novel Triangulenes: Computational Investigations of Energy Thresholds for Photocatalytic Water Splitting.

Organic materials with Inverted Singlet-Triplet (INVEST) gaps are interesting for their potential use in photocatalytic small molecule transformations such as the entirely solar-driven water splitting reaction. However, only a few INVEST emitters are thermodynamically able to split water requiring a first singlet excited dark state, S1 , above 1.27 or 1.76 eV, and absorption near solar the maximum, 2.57 eV. These requirements and the INVEST character are key for achieving a long-lived photocatalyst for water splitting. The only known INVEST emitters that conform to these criteria are large triangular boron carbon nitrides with unknown synthesis pathways. Using ADC(2), a quantum-mechanical method, we describe three triangulenes. 3 a is a cyano azacyclopenta[cd]phenalene derivative while 3 b and 3 c are cycl[3.3.3]azine derivatives. 3 b has a previously undescribed disulfide bridge. Overall, 3 a fulfills requirements for photocatalytic four-electron reduction of water while the S1 states of 3 b and 3 c are likely slightly low for the two-electron reduction process. By analyzing impacts of ligands, we find that there are guidelines describing how S1 -S5 energies and oscillator strengths, T1 energies, and ΔES1T1 gaps are affected, requiring deep-learning algorithms for which studies will be presented by us in due time. The impact of ground-state geometries, solvation effects, as well as reduced-cost ADC(2) algorithms on our findings are also discussed.

Building on the strengths of a double-hybrid density functional for excitation energies and inverted singlet-triplet energy gaps.

It is demonstrated that a double hybrid density functional approximation, ωB88PTPSS, that incorporates equipartition of density functional theory and the non-local correlation, however with a meta-generalized gradient approximation correlation functional, as well as with the range-separated exchange of ωB2PLYP, provides accurate excitation energies for conventional systems, as well as correct prescription of negative singlet-triplet gaps for non-conventional systems with inverted gaps, without any necessity for parametric scaling of the same-spin and opposite-spin non-local correlation energies. Examined over "safe" excitations of the QUESTDB set, ωB88PTPSS performs quite well for open-shell systems, correctly and fairly accurately [relative to equation-of-motion coupled-cluster singles and doubles (EOM-CCSD) reference] predicts negative gaps for 50 systems with inverted singlet-triplet gaps, and is one of the leading performers for intramolecular charge-transfer excitations and achieves near-second-order approximate coupled cluster (CC2) and second-order algebraic diagrammatic construction quality for the Q1 and Q2 subsets. Subsequently, we tested ωB88PTPSS on two sets of real-life examples from recent computational chemistry literature-the low energy bands of chlorophyll a (Chl a) and a set of thermally activated delayed fluorescence (TADF) systems. For Chl a, ωB88PTPSS qualitatively and quantitatively achieves DLPNO-STEOM-CCSD-level performance and provides excellent agreement with experiment. For TADF systems, ωB88PTPSS agrees quite well with spin-component-scaled CC2 (SCS-CC2) excitation energies, as well as experimental values, for the gaps between the S1 and T1 excited states.

Pandemic Use of Telehealth by Oncology at a Rural Academic Medical Center.

Introduction: The COVID-19 pandemic resulted in an exponential increase in telehealth. In response to the pandemic, Dartmouth-Hitchcock Health (D-HH) and its Norris Cotton Cancer Center (NCCC) closed non-essential in-person services on March 17, 2020 and began reopening on April 27, 2020. We examined outpatient telehealth utilization at D-HH and NCCC in the peri-pandemic period and compared utilization to the Academic Medical Center (AMC) overall and to other service lines. Methods: Weekly outpatient volumes, percentage telehealth, percentage video versus audio-only, and percentage of new patients were examined for D-HH, for the AMC, and for selected AMC-based service lines from January 1 to October 31, 2020. Results: Compared with the AMC overall and with five other primarily non-surgical specialties, oncology was lower in the (1) proportion of outpatient visits performed via telehealth (example week 7/12/20: oncology = 11%; AMC = 21%; mean of 5 other specialties = 38%) and (2) percentage of telehealth involving video versus audio-only (7/12/20: oncology = 19%; AMC = 58%; mean of 5 others = 60%). Oncology more closely resembled the surgical specialty of orthopedics (7/12/20: 2% telehealth; 10% of telehealth involved video). Oncology also demonstrated (1) a high proportion of outpatient visits involving procedures (oncology = 22%; orthopedics = 12%) and (2) no difference between telehealth and in-person visits in terms of the percentage involving new patients. Conclusions: During the peri-pandemic period, our oncology service demonstrated a lower than average incorporation of telehealth overall into their outpatient practice and a lower proportion of telehealth performed by video. Further understanding these results and the drivers behind them will be integral for redesigning outpatient oncology care with optimal integration of telehealth.

Time-Dependent Density Functional Theory Study of Copper(II) Oxo Active Sites for Methane-to-Methanol Conversion in Zeolites.

Copper-exchanged zeolites are useful materials for step-wise methane-to-methanol conversion (MMC). However, methanol yields on copper-exchanged zeolites are often modest, spurring interest in the development of active-site species that are activated at moderate temperatures, afford greater yields, and provide excellent methanol selectivities. Ultraviolet-visible (UV-vis) spectroscopy is a major tool for characterizing the active-sites and their evolution during the step-wise MMC process. However, computation of the UV-vis spectra of the copper-oxo active sites using Tamm-Dancoff time-dependent density functional theory (TDA-DFT) can be quite problematic. This has led to utilization of expensive methods based on multireference approaches, Green functions, and the Bethe-Salpeter equation. In this work, we examined the optical spectra of [CuO]+, [Cu2O]2+, [Cu2O2]2+, and [Cu3O3]2+ species implicated in MMC in zeolites. For the larger species, we examined how agreement with experimental data is improved with increasingly larger cluster models. For [CuO]+, we compared TDA-DFT against restricted active space 2nd-order perturbation theory, RASPT2. We found that signature peaks for [CuO]+ have multireference behavior. The excited states have many configuration state functions with a double excitation character. These effects are likely responsible for the poor utility of conventional TDA-DFT methods. Indeed, we obtain good agreement with experimental data and RASPT2 after accounting for 2h/2p excitations within TDA-DFT with a previously described configuration interaction singles and doubles, CIS(D)-style scheme. This was the case for [CuO]+, [Cu2O]2+, as well as a [Cu2O2]2+ species. Using a long-range corrected double-hybrid, ωB2PLYP, we provide for the first time computational evidence for the experimental UV-vis spectrum of the [Cu3O3]2+ active site motif.

Outpatient Virtual Visits and the "Right" Amount of Telehealth Going Forward.

Background: An exponential increase in outpatient telehealth visits occurred early in the pandemic period that has been followed by volumes that, although lower than peak numbers, are substantially greater than the pre-pandemic period. This provided an opportunity to assess provider perceptions regarding the right prevalence going forward and key obstacles to achieving it. Methods: A 10-question survey was distributed to all outpatient providers within the Dartmouth-Hitchcock Health System. Domains included practice location, specialty, professional degree, experience with telehealth, satisfaction, perception of the amount of telehealth that could be adequately delivered going forward, role of audio-only, and obstacles. Results: Three hundred thirty-six providers completed the survey representing 51 specialties. The most common response regarding the proportion of outpatient visits that could be delivered by video going forward was 21-50% (n = 104) followed by 6-20% (n = 99) and >50% (n = 71). A minority of respondents chose ≤5% (n = 17). In terms of the fraction of video visits for which phone was equally effective, a similar percentage of respondents felt that it was 1/10 (22%), 1/4 (20%), or 1/2 (26%) of visits. Fewer felt that all (7%) or 3/4 (15%) of visits were equally effective, and 10% felt that it was none. Common obstacles identified were the need for a physical exam, unique aspects of providers' patients, patient preference, and issues regarding technology and internet speed/connectivity. Conclusions: After a period of exponential growth in virtual visits due to the pandemic, outpatient providers within an academic health system felt that a substantial portion of future visits could be delivered by this modality.

Telehealth's New Horizon: Providing Smart Hospital-Level Care in the Home.

During the COVID-19 pandemic, medical providers have expanded telehealth into daily practice, with many medical and behavioral health care visits provided remotely over video or through phone. The telehealth market was already facilitating home health care with increasing levels of sophistication before COVID-19. Among the emerging telehealth practices, telephysical therapy; teleneurology; telemental health; chronic care management of congestive heart failure, chronic obstructive pulmonary disease, diabetes; home hospice; home mechanical ventilation; and home dialysis are some of the most prominent. Home telehealth helps streamline hospital/clinic operations and ensure the safety of health care workers and patients. The authors recommend that we expand home telehealth to a comprehensive delivery of medical care across a distributed network of hospitals and homes, linking patients to health care workers through the Internet of Medical Things using in-home equipment, including smart medical monitoring devices to create a "medical smart home." This expanded telehealth capability will help doctors care for patients flexibly, remotely, and safely as a part of standard operations and during emergencies such as a pandemic. This model of "telehomecare" is already being implemented, as shown herein with examples. The authors envision a future in which providers and hospitals transition medical care delivery to the home just as, during the COVID-19 pandemic, students adapted to distance learning and adults transitioned to remote work from home. Many of our homes in the future may have a "smart medical suite" as well as a "smart home office."

The WNT-controlled transcriptional regulator LBH is required for mammary stem cell expansion and maintenance of the basal lineage.

The identification of multipotent mammary stem cells (MaSCs) has provided an explanation for the unique regenerative capacity of the mammary gland throughout adult life. However, it remains unclear what genes maintain MaSCs and control their specification into the two epithelial lineages: luminal and basal. LBH is a novel transcription co-factor in the WNT pathway with hitherto unknown physiological function. LBH is expressed during mammary gland development and aberrantly overexpressed in aggressive 'basal' subtype breast cancers. Here, we have explored the in vivo role of LBH in mammopoiesis. We show that in postnatal mammary epithelia, LBH is predominantly expressed in the Lin(-)CD29(high)CD24(+) basal MaSC population. Upon conditional inactivation of LBH, mice exhibit pronounced delays in mammary tissue expansion during puberty and pregnancy, accompanied by increased luminal differentiation at the expense of basal lineage specification. These defects could be traced to a severe reduction in the frequency and self-renewal/differentiation potential of basal MaSCs. Mechanistically, LBH induces expression of key epithelial stem cell transcription factor ΔNp63 to promote a basal MaSC state and repress luminal differentiation genes, mainly that encoding estrogen receptor α (Esr1/ERα). Collectively, these studies identify LBH as an essential regulator of basal MaSC expansion/maintenance, raising important implications for its potential role in breast cancer pathogenesis.

Increased toll-like receptor 4 in cerebral endothelial cells contributes to the astrocyte swelling and brain edema in acute hepatic encephalopathy.

Astrocyte swelling and the subsequent increase in intracranial pressure and brain herniation are major clinical consequences in patients with acute hepatic encephalopathy. We recently reported that conditioned media from brain endothelial cells (ECs) exposed to ammonia, a mixture of cytokines (CKs) or lipopolysaccharide (LPS), when added to astrocytes caused cell swelling. In this study, we investigated the possibility that ammonia and inflammatory agents activate the toll-like receptor 4 (TLR4) in ECs, resulting in the release of factors that ultimately cause astrocyte swelling. We found a significant increase in TLR4 protein expression when ECs were exposed to ammonia, CKs or LPS alone, while exposure of ECs to a combination of these agents potentiate such effects. In addition, astrocytes exposed to conditioned media from TLR4-silenced ECs that were treated with ammonia, CKs or LPS, resulted in a significant reduction in astrocyte swelling. TLR4 protein up-regulation was also detected in rat brain ECs after treatment with the liver toxin thioacetamide, and that thioacetamide-treated TLR4 knock-out mice exhibited a reduction in brain edema. These studies strongly suggest that ECs significantly contribute to the astrocyte swelling/brain edema in acute hepatic encephalopathy, likely as a consequence of increased TLR4 protein expression by blood-borne noxious agents.

Decreased astrocytic thrombospondin-1 secretion after chronic ammonia treatment reduces the level of synaptic proteins: in vitro and in vivo studies.

Chronic hepatic encephalopathy (CHE) is a major complication in patients with severe liver disease. Elevated blood and brain ammonia levels have been implicated in its pathogenesis, and astrocytes are the principal neural cells involved in this disorder. Since defective synthesis and release of astrocytic factors have been shown to impair synaptic integrity in other neurological conditions, we examined whether thrombospondin-1 (TSP-1), an astrocytic factor involved in the maintenance of synaptic integrity, is also altered in CHE. Cultured astrocytes were exposed to ammonia (NH4Cl, 0.5-2.5 mM) for 1-10 days, and TSP-1 content was measured in cell extracts and culture media. Astrocytes exposed to ammonia exhibited a reduction in intra- and extracellular TSP-1 levels. Exposure of cultured neurons to conditioned media from ammonia-treated astrocytes showed a decrease in synaptophysin, PSD95, and synaptotagmin levels. Conditioned media from TSP-1 over-expressing astrocytes that were treated with ammonia, when added to cultured neurons, reversed the decline in synaptic proteins. Recombinant TSP-1 similarly reversed the decrease in synaptic proteins. Metformin, an agent known to increase TSP-1 synthesis in other cell types, also reversed the ammonia-induced TSP-1 reduction. Likewise, we found a significant decline in TSP-1 level in cortical astrocytes, as well as a reduction in synaptophysin content in vivo in a rat model of CHE. These findings suggest that TSP-1 may represent an important therapeutic target for CHE. Defective release of astrocytic factors may impair synaptic integrity in chronic hepatic encephalopathy. We found a reduction in the release of the astrocytic matricellular proteins thrombospondin-1 (TSP-1) in ammonia-treated astrocytes; such reduction was associated with a decrease in synaptic proteins caused by conditioned media from ammonia-treated astrocytes. Exposure of neurons to CM from ammonia-treated astrocytes, in which TSP-1 is over-expressed, reversed (by approx 75%) the reduction in synaptic proteins. NF-kB = nuclear factor kappa B; PSD95 = post-synaptic density protein 95; ONS = oxidative/nitrative stress.

Aquaporin-4 deletion in mice reduces encephalopathy and brain edema in experimental acute liver failure.

Brain edema and associated astrocyte swelling leading to increased intracranial pressure are hallmarks of acute liver failure (ALF). Elevated blood and brain levels of ammonia have been implicated in the development of brain edema in ALF. Cultured astrocytes treated with ammonia have been shown to undergo cell swelling and such swelling was associated with an increase in the plasma membrane expression of aquaporin-4 (AQP4) protein. Further, silencing the AQP4 gene in cultured astrocytes was shown to prevent the ammonia-induced cell swelling. Here, we examined the evolution of brain edema in AQP4-null mice and their wild type counterparts (WT-mice) in different models of ALF induced by thioacetamide (TAA) or acetaminophen (APAP). Induction of ALF with TAA or APAP significantly increased brain water content in WT mice (by 1.6% ± 0.3 and 2.3 ± 0.4%, respectively). AQP4 protein was significantly increased in brain plasma membranes of WT mice with ALF induced by either TAA or APAP. In contrast to WT-mice, brain water content did not increase in AQP4-null mice. Additionally, AQP4-null mice treated with either TAA or APAP showed a remarkably lesser degree of neurological deficits as compared to WT mice; the latter displayed an inability to maintain proper gait, and demonstrated a markedly reduced exploratory behavior, with the mice remaining in one corner of the cage with its head tilted downwards. These results support a central role of AQP4 in the brain edema associated with ALF.

Rac1b regulates NT3-stimulated Mek-Erk signaling, directing marrow-isolated adult multilineage inducible (MIAMI) cells toward an early neuronal phenotype.

Due to the limitations of neural stem cells to repair neuronal damage in the human brain, alternative approaches of repair using autologous adult stem cells have been examined for direct cell-replacement, or paracrine mediated neuroprotective effects. Human bone marrow-derived stromal cells (hMSCs) are a heterogeneous adult stem cell population with diverse immunomodulatory properties and the potential to differentiate into cells characteristic of all three germ layers. hMSCs are a renewable source of progenitor cells suitable for cell-based tissue repair. The marrow isolated adult multilineage inducible (MIAMI) cells developed by our laboratory are a developmentally immature homogeneous subpopulation of hMSCs that maintain self-renewal potential during ex vivo expansion, efficient differentiation capacity into neuron-like cells in vitro, as well as direct in vivo neuroprotection and functional recovery in animal models of neurological diseases. We now address the early signaling mechanisms regulating the neuron-like differentiation of MIAMI cells in vitro, in response to activation of the neurotrophic tyrosine-kinase receptor, type 3 (NTRK3) via neurotrophin 3 (NT3). We molecularly characterize a novel role for Rac1b mediating the neurogenic potential of MIAMI cells. Rac1b had an overall negative modulatory effect on the NT3-stimulated Mek1/2-Erk1/2 signaling pathway, proneuronal gene expression and neurite-like extensions. Rac1b was required for NT3-stimulated cell proliferation of MIAMI cells, yet was found to repress CCND1 and CCNB1 mRNA expression independent of NT3 stimulation, suggesting a dual neurotrophin dependent/independent function. Differential levels of Rac1b activity in hMSCs may explain the apparent contradictory reports regarding their neurogenic potential. These findings demonstrate the in vitro neurogenic potential of hMSCs as governed by Rac1b during NT3 stimulation.

Willingness to pay for a telemedicine-delivered healthy lifestyle programme.

INTRODUCTION: Effective weight-management interventions require frequent interactions with specialised multidisciplinary teams of medical, nutritional and behavioural experts to enact behavioural change. However, barriers that exist in rural areas, such as transportation and a lack of specialised services, can prevent patients from receiving quality care. METHODS: We recruited patients from the Dartmouth-Hitchcock Weight & Wellness Center into a single-arm, non-randomised study of a remotely delivered 16-week evidence-based healthy lifestyle programme. Every 4 weeks, participants completed surveys that included their willingness to pay for services like those experienced in the intervention. A two-item Willingness-to-Pay survey was administered to participants asking about their willingness to trade their face-to-face visits for videoconference visits based on commute and copay. RESULTS: Overall, those with a travel duration of 31-45 min had a greater willingness to trade in-person visits for telehealth than any other group. Participants who had a travel duration less than 15 min, 16-30 min and 46-60 min experienced a positive trend in willingness to have telehealth visits until Week 8, where there was a general negative trend in willingness to trade in-person visits for virtual. Participants believed that telemedicine was useful and helpful. CONCLUSIONS: In rural areas where patients travel 30-45 min a telemedicine-delivered, intensive weight-loss intervention may be a well-received and cost-effective way for both patients and the clinical care team to connect.

Factors Influencing Telemedicine Use at a Northern New England Cancer Center During the COVID-19 Pandemic.

PURPOSE: To characterize the use of telemedicine for oncology care over the course of the COVID-19 pandemic in Northern New England with a focus on factors affecting trends. METHODS: We performed a retrospective observational study using patient visit data from electronic health records from hematology-oncology and radiation-oncology service lines spanning the local onset of the pandemic from March 18, 2020, through March 31, 2021. This period was subdivided into four phases designated as lockdown, transition, stabilization, and second wave. Generalized linear mixed regression models were used to estimate the effects of patient characteristics on trends for rates of telemedicine use across phases and the effects of visit type on patient satisfaction and postvisit ER or hospital admissions within 2 weeks. RESULTS: A total of 19,280 patients with 102,349 visits (13.1% audio-only and 1.4% video) were studied. Patient age (increased use in age < 45 and 85 years and older) and urban residence were associated with higher use of telemedicine, especially after initial lockdown. Recent cancer therapy, ER use, and hospital admissions in the past year were all associated with lower telemedicine utilization across pandemic phases. Provider clinical department corresponded to the largest differences in telemedicine use across all phases. ER and hospital admission rates in the 2 weeks after a telehealth visit were lower than those in in-person visits (0.7% v 1.3% and 1.2% v 2.7% for ER and hospital use, respectively; P < .001). Patient satisfaction did not vary across visit types. CONCLUSION: Telemedicine use in oncology during the COVID-19 pandemic varied according to the phase and patient, medical, and health system factors, suggesting opportunities for standardization of care and need for attention to equitable telemedicine access.

Adoption of Telemedicine in a Rural US Cancer Center Amid the COVID-19 Pandemic: Qualitative Study.

BACKGROUND: The COVID-19 pandemic necessitated a rapid shift to telemedicine to minimize patient and provider exposure risks. While telemedicine has been used in a variety of primary and specialty care settings for many years, it has been slow to be adopted in oncology care. Health care provider and administrator perspectives on factors affecting telemedicine use in oncology settings are not well understood, and the conditions associated with the COVID-19 pandemic offered the opportunity to study the adoption of telemedicine and the resulting provider and staff perspectives on its use. OBJECTIVE: The aim of this paper is to study the factors that influenced telemedicine uptake and sustained use in outpatient oncology clinics at a US cancer center to inform future telemedicine practices. METHODS: We used purposive sampling to recruit a mix of oncology specialty providers, practice managers, as well as nursing and administrative staff representing 5 outpatient oncology clinics affiliated with the Dartmouth Cancer Center, a large regional cancer center in the northeast of United States, to participate in semistructured interviews conducted over 6 weeks in spring 2021. The interview guide was informed by the 5 domains of the Consolidated Framework for Implementation Research, which include inner and outer setting factors, characteristics of the intervention (ie, telemedicine modality), individual-level factors (eg, provider and patient characteristics), and implementation processes. In total, 11 providers, 3 leaders, and 6 staff participated following verbal consent, and thematic saturation was reached across the full sample. We used a mixed deductive and inductive qualitative analysis approach to study the main influences on telemedicine uptake, implementation, and sustainability during the first year of the COVID-19 pandemic across the 5 settings. RESULTS: The predominant influencers of telemedicine adoption in this study were individual provider experiences and assumptions about patient preference and accessibility. Providers' early telemedicine experiences, especially if negative, influenced preferences for telephone over video and affected sustained use. Telemedicine was most favorably viewed for lower-acuity cancer care, visits less dependent on physical exam, and for patient and caregiver education. A lack of clinical champions, leadership guidance, and vision hindered the implementation of standardized practices and were cited as essential for telemedicine sustainability. Respondents expressed anxiety about sustaining telemedicine use if reimbursements for telephonic visits diminished or ceased. Opportunities to enhance future efforts include a need to provide additional guidance supporting telemedicine use cases and evidence of effectiveness in oncology care and to address provider concerns with communication quality. CONCLUSIONS: In a setting of decentralized care processes, early challenges in telemedicine implementation had an outsized impact on the nature and amount of sustained use. Proactively designed telemedicine care processes with attention to patient needs will be essential to support a sustained role for telemedicine in cancer care.

Na-K-Cl cotransporter-1 in the mechanism of cell swelling in cultured astrocytes after fluid percussion injury.

Brain edema and associated increased intracranial pressure are major consequences of traumatic brain injury (TBI). An important early component of the edema associated with TBI is astrocyte swelling (cytotoxic edema). Mechanisms for such swelling, however, are poorly understood. Ion channels/transporters/exchangers play a major role in cell volume regulation, and a disturbance in one or more of these systems may result in cell swelling. To examine potential mechanisms in TBI-mediated brain edema, we employed a fluid percussion model of in vitro barotrauma and examined the role of the ion transporter Na(+)-K(+)-2Cl(-)-cotransporter 1 (NKCC1) in trauma-induced astrocyte swelling as this transporter has been strongly implicated in the mechanism of cell swelling in various neurological conditions. Cultures exposed to trauma (3, 4, 5 atm pressure) caused a significant increase in NKCC1 activity (21%, 42%, 110%, respectively) at 3 h. At 5 atm pressure, trauma significantly increased NKCC1 activity at 1 h and it remained increased for up to 3 h. Trauma also increased the phosphorylation (activation) of NKCC1 at 1 and 3 h. Inhibition of MAPKs and oxidative/nitrosative stress diminished the trauma-induced NKCC1 phosphorylation as well as its activity. Bumetanide, an inhibitor of NKCC1, significantly reduced the trauma-induced astrocyte swelling (61%). Silencing NKCC1 with siRNA led to a reduction in trauma-induced NKCC1 activity as well as in cell swelling. These findings demonstrate the critical involvement of NKCC1 in the astrocyte swelling following in vitro trauma, and suggest that blocking NKCC1 activity may represent a useful therapeutic strategy for the cytotoxic brain edema associated with the early phase of TBI.

Neuroprotective properties of marrow-isolated adult multilineage-inducible cells in rat hippocampus following global cerebral ischemia are enhanced when complexed to biomimetic microcarriers.

Cell-based therapies for global cerebral ischemia represent promising approaches for neuronal damage prevention and tissue repair promotion. We examined the potential of marrow-isolated adult multilineage-inducible (MIAMI) cells, a homogeneous subpopulation of immature human mesenchymal stromal cell, injected into the hippocampus to prevent neuronal damage induced by global ischemia using rat organotypic hippocampal slices exposed to oxygen-glucose deprivation and rats subjected to asphyxial cardiac arrest. We next examined the value of combining fibronectin-coated biomimetic microcarriers (FN-BMMs) with epidermal growth factor (EGF)/basic fibroblast growth factor (bFGF) pre-treated MIAMI compared to EGF/bFGF pre-treated MIAMI cells alone, for their in vitro and in vivo neuroprotective capacity. Naïve and EGF/bFGF pre-treated MIAMI cells significantly protected the Cornu Ammonis layer 1 (CA1) against ischemic death in hippocampal slices and increased CA1 survival in rats. MIAMI cells therapeutic value was significantly increased when delivering the cells complexed with FN-BMMs, probably by increasing stem cell survival and paracrine secretion of pro-survival and/or anti-inflammatory molecules as concluded from survival, differentiation and gene expression analysis. Four days after oxygen and glucose deprivation and asphyxial cardiac arrest, few transplanted cells administered alone survived in the brain whereas stem cell survival improved when injected complexed with FN-BMMs. Interestingly, a large fraction of the transplanted cells administered alone or in complexes expressed ßIII-tubulin suggesting that partial neuronal transdifferentiation may be a contributing factor to the neuroprotective mechanism of MIAMI cells.

A multicenter comparison of established and emerging cardiac biomarkers for the diagnostic evaluation of chest pain in the emergency department.

BACKGROUND: The aim of this study is to assess the role of novel biomarkers for the diagnostic evaluation of acute coronary syndrome (ACS). METHODS: Among 318 patients presenting to an emergency department with acute chest discomfort, we evaluated the diagnostic value of 5 candidate biomarkers (amino terminal pro-B-type natriuretic peptide [NT-proBNP], ischemia modified albumin, heart fatty acid binding protein, high-sensitivity troponin I [hsTnI], and unbound free fatty acids [FFAu]) for detecting ACS, comparing their results with that of conventional troponin T (cTnT). RESULTS: Sixty-two subjects (19.5%) had ACS. The sensitivity and negative predictive values of NT-proBNP (73%, 90%) and hsTnI (57%, 89%) were higher than that of cTnT (22%, 84%). Unbound free fatty acids had the highest overall combination of sensitivity (75%), specificity (72%), and negative predictive values (92%) of all the markers examined. A significant increase in the C-statistic for cTnT resulted from the addition of results for NT-proBNP (change 0.09, P = .001), hsTnI (change 0.13, P < .001), and FFAu (change 0.15, P < .001). In integrated discrimination improvement and net reclassification improvement analyses, NT-proBNP, hsTnI, and FFAu added significant diagnostic information to cTnT; when changing the diagnostic criterion standard for ACS to hsTnI, FFAu still added significant reclassification for both events and nonevents. In serial sampling (n = 180), FFAu added important reclassification information to hsTnI. CONCLUSION: Among emergency department patients with symptoms suggestive of ACS, neither ischemia modified albumin nor heart fatty acid binding protein detected or excluded ACS, whereas NT-proBNP, hsTnI, or FFAu added diagnostic information to cTnT. In the context of hsTnI results, FFAu measurement significantly reclassified both false negatives and false positives at baseline and in serial samples.

EGF and bFGF pre-treatment enhances neural specification and the response to neuronal commitment of MIAMI cells.

AIMS: Multipotent mesenchymal stromal cells raise great interest for regenerative medicine studies. Some MSC subpopulations have the potential to undergo neural differentiation, including marrow isolated adult multilineage inducible (MIAMI) cells, which differentiate into neuron-like cells in a multi-step neurotrophin 3-dependent manner. Epidermal and basic fibroblast growth factors are often used in neuronal differentiation protocols for MSCs, but with a limited understanding of their role. In this study, we thoroughly assessed for the first time the capacity of these factors to enhance the neuronal differentiation of MSCs. MATERIALS AND METHODS: We have characterized MIAMI cell neuronal differentiation program in terms of stem cell molecule expression, cell cycle modifications, acquisition of a neuronal morphology and expression of neural and neuronal molecules in the absence and presence of an EGF-bFGF pre-treatment. RESULTS: EGF-bFGF pre-treatment down-regulated the expression of stemness markers Oct4A, Notch1 and Hes5, whereas neural/neuronal molecules Nestin, Pax6, Ngn2 and the neurotrophin receptor tyrosine kinase 1 and 3 were up-regulated. During differentiation, a sustained Erk phosphorylation in response to NT3 was observed, cells began to exit from the cell cycle and exhibit increased neurite-like extensions. In addition, neuronal ß3-tubulin and neurofilament expression was increased; an effect mediated via the Erk pathway. A slight pre-oligodendrocyte engagement was noted, and no default neurotransmitter phenotype was observed. Overall, mesodermal markers were unaffected or decreased, while neurogenic/adipogenic PPARγ2 was increased. CONCLUSION: EGF and bFGF pre-treatment enhances neural specification and the response to neuronal commitment of MIAMI cells, further increasing their potential use in adult cell therapy of the nervous system.